The discovery of an effective treatment for renal anemia

In 1986 recombinant erythropoietin is the product of years of research

Anaemia was a major cause of morbidity in patients with end stage renal disease until recombinant erythropoietin became available at the end of  the 1980s. 
Before long-term dialysis was available, haemoglobin (Hb) levels fell to a mean of about 8 g/dl at a glomerular filtration rate (GFR) of 10ml/min, and about 7 g/dl at a GFR of 5, with a significant minority of patients running levels below 5 g/dl. 

The anaemia of renal failure in a pre-dialysis and pre-EPO
study.  Mishra and Kerr,  with permission.

Dialysis alone elevated Hb a little, but many patients were severely symptomatic and disabled by their anaemia.  Androgens and other treatments were in use but had only slight impact.  Blood transfusions raised Hb to relieve the worst symptoms or life-threatening crises, but were problematic for long term use because:

• Weekly or alternate weekly treatment was commonly required
• Iron overload was a serious consequence of regular transfusions 
• Antibody formation made blood increasingly difficult to match
• Sensitization to transplant antigens could preclude later transplantation
• Risks of transmission of viral infections (hepatitis devastated renal units 1964-72)

For these reasons, transfusion to near-normal haemoglobin values was not feasible and many patients lived with chronic severe anaemia. 

The full explanation for renal anaemia was controversial.  It was known that red cells had shortened survival in renal failure.  Regular blood loss was an additional factor for haemodialysis patients.  However the more severe anaemia of patients who had had bilateral nephrectomies suggested that something produced by the kidneys was important. 
Many pieces of scientific work led to the discovery of Erythropoietin (EPO), which was purified from urine in 1977.  Assays to measure it were developed in the 1980s, and showed that although renal patients produced some erythropoietin, levels failed to rise as they did in patients with anaemia of other causes.

EPO was a revolutionary treatment for these relatively young patients.  Recombinant EPO became the first blockbuster of a new generation of genetically engineered protein drugs.  But it was extremely expensive, adding about £5000 per annum, over 30% of the cost of dialysis in 1990.  Subcutaneous administration and increased iron therapy were subsequently found to be ways to reduce the amounts needed and minimize cost.

Recommendations from the UK Renal Association in 1990 were that EPO should be given to patients with Hb below 8g/dl, or who were transfusion dependent or had their lives threatened by anaemia, or were at risk of sensitization to transplant antigens because of their transfusion requirement.  It was hoped that this would note extend to more than 20% of dialysis patients. 

Today's patients are older and have more comorbid disease than the patients treated 15-20 years ago.   They tolerate low haemoglobins less well and arguably have more to gain from successful treatment of anaemia.  This led to an edging up of target haemoglobins, supported by mostly pharma-sponsored research that showed improved activity and well-being in patients whose Hb was lifted over 10. ‘Minimum acceptable’ haemoglobin levels were identified in guidelines.  The proportion of haemodialysis patients receiving EPO or similar agents rose to 90%.

Testing of whether these higher targets were safe came late, and wasn’t so encouraging.  Beginning with the Normal Haematocrit Study in 1998, and culminating in the CHOIR and CREATE studies in 2006, it became apparent that although having normal haemoglobins seemed to make patients feel better, it might be at the cost of increased thrombotic events, death, and cancer.  No safe dose of EPO, or safe Hb limit that can completely prevent these adverse effects has been established. 

ESAs (meaning Erythropoiesis Stimulating Agents of all types, including recombinant EPO) are now a core part of the management of advanced CKD. They have been hugely beneficial, and national and international guidelines assume their use.  But how to balance the benefits with the potential long-term risks is still not solved. 


Further reading

Cotes PM 1982 Immunoreactive erythropoietin in serum. I. Evidence for the validity of the assay method and the physiological relevance of estimates  Br J Haematol 50:427-38
Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. 1987. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med. 316:73-8.
Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. 1986. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet. 1986 328:1175-8.
Goldsmith DJA, CG Winearls.  2008.  EPO – taken for granted now, but 20 years ago a new era was dawning.  UK Renal Association.  (not available online)

Surprises from the 1994 Modification of Diet in Renal Disease (MDRD) study

Low-protein disappoints; attention drawn to proteinuria and blood pressure

The MDRD study was a landmark trial set up to prove the importance of dietary protein in slowing the progression of kidney failure.  This had been shown in animal models but human studies were not so clear.  It was combined with using two different blood pressure targets, as again these seemed important in animal studies but it was not clear how much we should lower blood pressure in patients.

Patients were recruited from nephrologists and by advertisement; they were known to have a kidney diagnosis. They were not simply people found to have reduced kidney function by random testing.  Diabetic nephropathy was excluded but diagnoses were varied.  25% had glomerulonephritis.  Almost as many had the genetic condition polycystic kidney disease (PKD, a group you might think whose outcome would not be altered so much by control of diet or blood pressure. 

The patients were divided into these groups with higher or lower protein intake, and higher or lower blood pressure: 

Study	GFR	Protein intake	Blood pressure
1 (n = 585)	25-55	Usual protein (1.3 g/kg/d)   or Low protein (0.58 g/kg/d)	140/90   or 130/80
2 (n = 255)	13-24	Low protein (0.58 g/kg/d)   or Very low (0.28 g/kg/d)	140/90   or 130/80

The very low protein diet was supplemented with essential keto acids and amino acids.  Glomerular filtration rate (GFR) was measured every 4 months by iothalamate clearance and normalised for surface area (/1.73m2). Follow up was for an average of 2.2 years. 

The Results were surprising
Diet had no impact on rate of loss of GFR or on the number of patients starting dialysis or dying, in either the low or the high GFR groups.
Blood pressure control had no overall effect, but there was a striking benefit from the lower blood pressure target for those with over 1g of proteinuria per day.  The benefits increased further as the amount of proteinuria rose. 

Decline in GFR in study 1.  Usual protein group is the dashed
line and low-protein the solid line.  No significant difference.
There was an early fall then slower gradient in the low-protein
group but no overall benefit. 

Deaths and ESRD in study 2.  Very low protein is the solid

line, low protein is the dashed line.  Figures from Klahr et
al as below, with permission from NEJM.

Diet enthusiasts have hoped that there might be a silver lining, but one has not emerged.  If there is any long term effect, it seems to be slight.  Worse, a 10 year analysis of what happened in the low-GFR group (Study 2) showed that those who had been allocated to the very low protein diet started dialysis no later than the low protein group, but were twice as likely to have died (Menon 2008).  The effect seemed to persist long after the study had finished.  Surely the last nail in the coffin of very low protein diets, and confirming Thomas Addis's caution about low protein diets in 1949, 'We are trying to do something dangerous'. 
What else did the trial achieve?  Well scores of other studies have come from analysing the details of the rich data collected in the MDRD study.  The best known is the MDRD equation, a formula for estimating GFR from serum creatinine which is now in near universal use.  
A couple of interesting subgroup analyses were mentioned in the original paper.  Patients with polycystic kidney disease did not appear to benefit from blood pressure control.  The 53 black patients had a higher rate of loss of GFR than other patients, but it was half the rate in those allocated to the lower blood pressure target group.

Why were the diet results so negative?  The conclusion should be qualified: it was not that diet is useless.  It was that lowered protein diets are not helpful in well supervised patients with good blood pressure control.  Even the higher blood pressure group in MDRD had pretty good blood pressure control.  Animals with renal failure probably have comparatively much higher pressures. 

How high can protein intake safely be?  With those animal experiments in mind, plus a number of concerning anecdotes about the effects of protein supplementation on kidney disease in some individuals, few dare to recommend exceeding 'moderate' protein intake. 
Personal view:  If blood pressure control is poor or supervision difficult, you might argue for lower intakes.  If you cannot or do not want to use dialysis to control symptoms in advanced uraemia, targets could be lower still.  

Further reading
Diets for chronic uraemia - on this blog
Klahr S et al.  The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease.  New Engl J Med 1994 330:877-84
Menon V et al.  Effect of a very low protein diet on outcomes: long-term follow-up of the MDRD study.  Am J Kidney Dis 2009 53:208-17.

Twins in transplantation

Groundbreaking - and lucky to have one

John Merrill shows the Herrick twins an early dialysis machine

On December 23rd 1954, 24 year-old Richard Herrick became the first successful kidney transplant recipient in Boston, Massachusetts. He was lucky both to be in Boston, and to have an identical twin brother Ronald who was prepared to take the risk to help him, as at that time the problems of rejection were known but not soluble.
Joseph Murray, the surgeon, had perfected the surgical technique in dogs.  The kidney was anastamosed onto the iliac blood vessels in the pelvis outside the peritoneum, as originally developed in France.  Much the same operation is used today.  Murray had already undertaken 20 transplants of cadaver kidneys into dying patients, usually into the groin and with admission to patients of their experimental nature, but none of them successfully. 
The recovery of Richard Herrick's health, anaemia and nutritional state were remarkable.  He died of a heart attack 8 years later, while his genetically identical brother lived 56 years longer until December 2010, perhaps an early pointer to the cardiovascular consequences of kidney disease.


Edith Helm was 20 and just married in Oklahoma in 1956 when she was told she was dying of renal failure.  However she had a twin, Wanda, and later that year travelled to Boston to become the first woman to receive a successful transplant.  Before the operation the sisters were visited by Richard Herrick.  As she was leaving the hospital in August 1956, she said 'Ive never been operated on before, never been east before, never been on a plane before. This has really been an experience'  She lived 54 more years until April 2011, going to work as a school cook, and becoming the first transplant patient to give birth, having a son and a daughter. 

A total of 12 identical twin grafts had been carried out in Boston by 1961, 35 around the world by 1965.  In long term follow-up, 4 of the first 7 died later of renal failure following the recurrence of nephritis in their grafts, in the absence of immunosuppression. 

The UK's first successful transplant was between 49 year old identical twins in October 1960.  Means to prove that they were identical are described in detail in Woodruff's 1961 paper, and were essentially the same as used by Murray and Merrill in Boston, based on appearance, fingerprint patterns (undertaken by local police in Boston), detailed blood grouping, haptoglobin variants, and finally on skin grafting.  A square of skin was taken from each twin and transplanted to the other.  This proof of immunological identity and tolerance between identical twins was first demonstrated in 1937.

Reciprocal skin grafts between the
Edinburgh identical twin brothers

Skin grafts like this were used to prove tolerance between a pair of non-identical (male and female) twins who had exchanged some bone marrow in utero.  Very unusually their blood showed two blood types: the man had 86% group A red cells and 14% group O, while the woman had 99% O and 1% A.  The skin grafts were not rejected (Woodruff 1959). This provided evidence that tolerance might be achievable without drugs one day.   Experience in twins suggests it could be at the expense of a higher incidence of disease recurrence. 

Many different approaches to suppressing rejection were investigated in these early days and modern regimens were arrived at step by step, with azathioprine being the first key success after the failure of irradiation treatment.


Further reading
Murray JE, MP Merrill, JH Harrison.  Renal homotransplantation in identical twins.  J Am Soc Nephrol 12:201-4 (reprinted from Surg Forum 1955 VI: 432-6)
Woodruff MFA, JS Robson, JA Ross, B Nolan, AT Lambie.  Transplantation of a kidney from an identical twin.  Lancet 1961 ii 1245-9
Murray JE. Human organ transplantation: background and consequences. (from Nobel Prize Lecture 1990).  Science 1992 256:1411-15
Woodruff MFA, B Lennox. Reciprocal skin grafts in a pari of twins showing blood chimaerism. Lancet 1959 ii 476-8
Tilney NL. Renal transplantation between identical twins: a review.  World J Surg 1986 10:381-8

Diets for chronic uraemia

1949-1993:  Addis to Giovannetti

It didn’t work for her: a 46 year old female patient who stopped

her diet. Note that it was lowering urea but not creatinine.

From Shaw et al 1965, by kind permission of OUP.

Low protein diets were shown to prolong the life of uraemic rats in experiments in the 1930s, and it was long held that the products of protein metabolism (which included Urea) were major contributors to the symptoms and signs of uraemia.  In the late 1940s, no-protein no-electrolyte diets, the Borst and Bull regimens, were introduced for conservative management of acute renal failure. 

Thomas Addis was a strong proponent of low protein intake for chronic uraemia too.  In his classic 1949 book Glomerular Nephritis he talked of ‘resting the kidney’, perhaps now interpreted as reducing hyperfiltration, and carefully explained how to achieve it in partnership with patients, dietitians and nurses in the real world. However he also commented

“We are trying to do something dangerous.  We are always on the edge of a possible deficiency”. 

Referring back to data from the 1920s, when the minimum protein intake compatible with neutral nitrogen (protein) balance was estimated, he prescribed 0.5g of protein per kg weight per day.  This was increased by any amount lost in urine, and a bit more was alllowed for growing children.  These principles became widely accepted and followed. 

Giordano in 1961 was probably the first to advocate a much lower protein intake, 18g, with supplementation of essential amino acids, but this idea became more widely associated with the name of Giovannetti after a 1964 paper in The Lancet.  It is interesting that this more extreme management came into vogue just at the time that dialysis and transplantation were beginning to develop.  Perhaps there was increased awareness of end stage renal disease, and it was all too obvious who could not be eligible for these new experimental and expensive treatments.  The aim was to reduce the symptoms and prolong the life of patients with advanced and terminal uraemia, when symptoms could be severe on more moderate protein restriction.

Giovannetti’s patients were 27-52 years old and had creatinine levels of 900-1600 micromol/l (10-18 mg/dl) on admission.  Some of them needed temporary dialysis (the only kind available most likely) to stop vomiting before they could start their diet, but then symptoms improved.  The severity of renal failure in their patients is apparent from their report.  Two of 8 died but the others remained alive at 10 months. 

The diet

Attempts to simplify the regimen, and make it more acceptable in the Northern Europe of the time by replacing the starch-based spaghetti with bread recipes designed for patients with phenylketonuria, were described by Berlyne and colleagues in Manchester in 1965.  Glomerular filtration rates varied from 1 to 5 ml/min.  Those with values greater than 2.5 ml/min tended to do better.  They reported lowered urea and phosphate and improved (but persistent) acidosis, and perhaps most importantly, reduced anorexia, nausea and vomiting.  In a later paper they also described less drowsiness so that patients tended to die in a bleeding-agitation syndrome, which doesn’t sound such a great success. On this diet death occurred when creatinine was over 1800 micromol/l (20 mg/ml), urea a mean of 80 mmol/l (230 mg/dl) (see Figure).  Urea:creatinine levels were generally lower on very low protein diets. 
All groups commented on the unpalatability of these diets (click on the diet sheet image to the right) and how difficult patients found it to adhere to them, and to maintain adequate intake, although they seemed to achieve their purpose in the short term. 

A number of mostly small and flawed human studies during the 1980s supported that low protein diets reduced the rate of loss of function in patients, a conclusion supported by further animal experiments.  However it was not until the Modification of Diet in Renal Disease (MDRD) study in 1994 that the real value of low protein diets in human kidney disease became known.  And the answer was not at all what was expected. 

Further info
Conservative dietary management from edren (www.edren.org)
Addis T.  Glomerular Nephritis.  Macmillan (New York) 1949. 
Shaw AB, FJ Bazzard, EM Booth, S Nilwarangkur, GM Berlyne.  The treatment of chronic renal failure by a modified Giovannetti diet.  Quart J Med 1965 34:237-53
Giordano C.  Treatment of uraemia using essential amino acid and low protein diets. 1963 Proceedings of the 2nd International Congress of Nephrology 752-7
Giordano C.  Protein restriction in chronic renal failure.  Kidney Int 1982 22:401-8
Giovannetti S, Q Maggiore.  A low-nitrogen diet with proteins of high biological value for severe chronic uraemia.  1964 Lancet 1964 i 1000-1003

The record holders

A few patients have been on renal replacement therapy for over 45 years

The Royal Free programme
This photograph of 'The Lucky Thirteen' taken in 1965 shows patients treated at the UK's first centre for long-term dialysis at the Royal Free Hospital, London, with their consultant Dr Stanley Shaldon (centre, front row).  Olga Hepple, left of Dr Shaldon, featured in a Pathe film of very early home haemodialysis in the UK.  Three of them featured in the first episode of the BBC's Tomorrow's World in 1965, which you can see online, a remarkable historical record.

Ray Jones (extreme left of the front row; called 'Ronnie' in the TV prog) began haemodialysis at the age of 34 in 1963 using Stanley Shaldon's dual femoral catheter system, a tube in the artery and vein in the groin.  The other three patients who started at this time did not survive the year, but Ray survived nearly 29 years until 1991 and was in the Guinness book of records in 1989 as the world's longest survivor sustained by only haemodialysis.  He never had home dialysis, but continued to work until he was in his 60s.  His wife Joan continues to campaign for Kidney Research UK.

Second from the right on the front row is Robin Eady, who is the world record holder.  Robin began treatment in Seattle in February 1963, when he was taken ill as a 21 year-old medical student and found to have advanced renal failure.  He was put on an extremely limited diet and expected to die.  However Life and Paris Match magazines had featured the first dialysis for end stage renal failure undertaken in Seattle by the group led by Belding Scribner.  Robin was allowed treatment as he was to be trained as a technician to take the technique elsewhere. After 4 months he went on to the very new programme in Edmonton, Canada, for 18 months before coming back to the Royal Free programme in December 1964.  Subsequently he returned to medical school and moved to Guy's, where he met he met his future wife Ann who was one of the first dialysis nurses.  During his training he returned to Seattle for a year in 1973.  He had home haemodialysis for many years until finally accepting a kidney transplant in 1987.  He became Professor of Dermatology, retiring only recently, and in September 2011 he and Sir Peter Morris, his transplant surgeon, both attended Kidney Research UK's 50th Anniversary meeting in Edinburgh.  More on early dialysis in the UK

Robin Eady 1966

The Seattle Programme
Robin Eady received his twice weekly 12-hour treatments alongside Clyde Shields, the first long-term dialysis patient in the world, who had commenced treatment in 1960, and two other patients.  He is the only survivor from these very early days.  More on Seattle and the beginnings of long term HD.   More about Seattle history from Seattle.

Peter Lundin became a medical student two years after starting dialysis in Seattle in 1966, giving himself home nocturnal haemodialysis for 10 hours three times a week throughout his time at Stanford.  He was on haemodialysis for most of his remaining life apart from 6 years transplanted in the 1990s, and had the same arteriovenous fistula for over 30 years.  There are many testaments to the inspiring example he gave to other patients facing end stage renal failure.  He became a professor of medicine, and a member of the group developing the K/DOQI treatment standards.  He died in 2001 after 35 years of treatment.  

Nancy Spaeth was accepted by the Life and Death Committee in Seattle in 1966, and after two years of in-centre treatment embarked on home haemodialysis.  She recalls attending fund-raising events for Dr Scribner, Dr Henry Tenchkhoff holding her first baby, and participation in Dr Joseph Eschbach's first study of erythropoietin treatment.  She had 4 transplants and two children, so has experience of all the ups and downs, and most of the different peritoneal and haemodialysis regimens. 

Others from the mid 1960s
There are of course many more remarkable stories.  In Edinburgh two patients are at or close to their 45th anniversary of renal replacement therapy. 

Brian Tocher began treatment at Fulham Hospital (subsequently Charing Cross) in 1966, briefly intermittent PD then HD, with a few years of transplantation. Patricia LeBlack came from Guyana to London to work and began treatment at the Royal Free Hospital shortly after, but never had a transplant.

Most patients with such long survival have spent long periods transplanted.  However Stephen Rifkin listed several patients with over 33 years of haemodialysis experience in a Medscape article in 2008. 
Omitted from that list was Jean who commenced treatment in Oxford in 1966, thirteen years after experiencing Henoch Schonlein purpura, so presumably because of IgA nephropathy.  She refused a transplant because she feared the side effects of steroids, and by the time of her death after 35 years in 2001 had experienced about 5,000 dialysis sessions and over 50 surgical procedures.  During her final illness it was observed that only one member of staff had been alive (as a schoolboy) when she started treatment. 

What do they have in common?
All recognise that they have been lucky.  In the early days, it wasn't easy to get dialysis but the struggle to get onto treatment was just the beginning.  All are grateful for the opportunities that they did not expect to have, and to their families and the medical teams that shared these struggles. 

All of the very long term survivors have spent long periods transplanted, but it is interesting that several of them waited years or decades before their first.  This may have saved them, as the risks of transplantation in the early years were extremely high.  None of the very early transplant recipients are still alive. Most longterm survivors have had long periods of very long-hours dialysis, and this may be important too. 

Those I have met are remarkably tolerant of the young renal unit staff members who believe they know so much about the management of renal failure.  It is difficult to know how much their personalities have been moulded by the circumstances, but all of them have been careful and have complied with the treatments suggested most of the time, without being so overtly obsessional that it has completely dominated their lives. 

All of them have the most remarkable stories, many have had miraculous escapes, most have had very eventful lives.  Many renal patients have extraordinary stories, but if you know patients with the longest histories, ask them about their early days.  They have a lot to teach us. 

We would be interested to hear any updates or additions.  Please post in Comments below or send to renal@ed.ac.uk


Further info
On the historyofnephrology blog:  Early HD; and early transplantation
Eady R  Survival is not enough: reflections of a long-term renal patient.  J Nephrol (2008) 21:S3-S6.
Friedman EA, J Bommer.  Peter Lundin (1944-2001) the physician/patient role model.  Nephrol Dial Transplant (2001) 16:2272
Rifkin SI  Thirty-seven uninterrupted years of haemodialysis: a case report.  http://www.medscape.com/viewarticle/580265
Spaeth N  The nurse, mother of two and four transplants - Nancy Spaeth tells her story.  Nephrol Dial Tranpslant (2007) 22:64-7
Winearls CG, CW Pugh.  Staying one step ahead - one patient's dialysis experience.  British Journal of Renal Medicine (2003) 6-9

A version of this article will appear in the Journal of Renal Nursing. 

Transplantation takes off in the mid 1960s

Years of experimentation finally pay off

Roy Calne (white coat) with dogs Tweedledee, 

Titus and Lollipop, recipient of the first successful long-term

organ transplant, using azathioprine (Copyright of and with
permission from Sir Roy Calne -  link to source)

Transplantation only began to be a real prospect for patients with chronic renal failure in the mid 1960s, after many, many unsuccessful attempts.  Success with several pairs of identical twins (when one had kidney failure and the other didn’t) showed that the technical problems, largely worked out in dogs, had been solved.  However the problems of rejection had not.  (see First transplants post)

Frank Burnet and Peter Medawar won the 1960 Nobel Prize in Medicine for work that defined rejection and immune tolerance.  Medawar worked in the Glasgow Burns Unit on skin grafting during the Second World War, and subsequently with Burnet.  He came to believe that the problem of rejection could  not be solved.  Certainly in the early 1960s there was no way of suppressing rejection without usually killing the patient, as many attempts showed.  Whole body irradiation was transiently adopted, then there were experiments with various drugs including corticosteroids, cyclophosphamide and thiopurine, sometimes with brief or isolated successes.

As long-term dialysis was scarcely available or even thought of before this time, the high risks of these early transplants were felt to be justified.  Several of the UK’s early dialysis units were established by transplant surgeons to support the patient temporarily.  After work by Roy Calne in dogs, an analogue of thiopurine, azathioprine, was first used in human transplantion 1962, in Boston and then in Edinburgh, both successfully.  However toxicity was still high and further deaths followed.

As experience with these new drugs developed, lower doses of azathioprine were used in combination with steroids (prednisolone or prednisone).  By 1965, 1 year survival rates of cadaver grafts were over 60%, with live related grafts higher still.  Dr Molly McGeown in Belfast pioneered a highly successful regimen using lower doses of prednisolone, 20mg per day from day 1, and this was taken up widely in other centres during the 1970s.  However the Belfast results remained strikingly good, much better than other centres, showing that it wasn’t just what you used, but how you did it – the elusive ‘centre effect’.  The Belfast results reported in 1977 showed 82% two-year survival from 102 transplants in 93 patients 1958-77; a level of success that many units struggled to match until several years after the next major anti-rejection milestone, the introduction of Cyclosporin.  This was first approved for use (and it took some getting used to) in 1983 after trials led by Roy Calne in Cambridge in 1978-9.

Four other developments were important before Cyclosporin came into general use.

A vial of anti-lymphocyte 

globulin made in horses

in Edinburgh in 1972 

(first used there late 1960s) 

A new anti-rejection tool introduced in the 1960s was anti-lymphocyte serum, antibodies raised in rabbits or horses to kill human lymphocytes, which had been developed during the 1950s and 60s.

‘Cross-matching’ using white blood cells to prevent hyperacute rejection was described by Terasaki in 1965, and the basis of tissue typing and its impact on graft survival was mapped out from then.  The benefits of tissue type matching with modern drugs are smaller but still detectable.

In 1974 Terasaki also reported that patients who had received blood transfusions were less likely to reject their transplants.  There was understandable reluctance to introduce deliberate transfusion policies in the light of previous experience on dialysis units with hepatitis, and the risk of sensitisation to tissue type antigens, but in the azathioprine/prednisolone era the effect was quite substantial so it was adopted by most units.  With modern drugs it is no longer a powerful effect and has been abandoned again.

The fourth and final developments were medicolegal, increasingly allowing the use of cadaver donors, which formed the great majority of transplants in this era.

It is striking that the core tools of transplantation in the 1960s, azathioprine and steroids and anti-lympocyte antibodies, and the basic surgical technique, are still in use today.  The major pharmaceutical modification has been the addition of the calcineurin inhibitor Cyclosporin and later Tacrolimus.  Azathioprine has been partially supplanted by an equivalent drug Mycophenolate.  More specific and targeted antibodies of various kinds are also in use, though many of these have yet to find a firm place.  The ambition of inducing tolerance so that the patient does not require long term immunosuppression is closer, but has still not been achieved for human transplantation.

In 1988 McGeown was reporting that Belfast’s 10 year graft survival was 55%, and patient survival was 67%.  Death with a functioning graft was becoming an important issue, with most deaths occurring not from kidney disease, but from cardiovascular causes.  With most units now using Cyclosporin and beginning to aspire to this sort of long-term success rate, the possibility of moving on to think about long-term problems marked the beginning of the modern transplant era.  

Further info

Sir Peter Medawar's Nobel Prize lecture (Nobel Prize website) 

History of transplantation (with a UK bias) from the BTS 

Roy Calne.  Recollections from the Laboratory to the Clinic. In: Terasaki PI (ed) History of Transplantation: thirty-five recollections.  UCLA Press, 1991

Starzl TE.  The development of clinical renal transplantation.  Am J Kid Dis 1009 6:548-56

Murray JE.  Human organ transplantation: background and consequences (from Nobel prize lecture 1990).  Science 1992 256:1411-15
Transplantation in Edinburgh from www.edren.org
Dialysis and transplantation in Belfast by Mollie McGeown; and a 1998 interview with Dr McGeown (ISN videolegacy project)

An article based on this post will appear in the Journal of Renal Nursing in August 2011.  

Diet for acute renal failure in the 1940s

The beginning of the multidisciplinary renal team

In 1949 Thomas Addis described the anarchy that existed in recommendations for the management of acute glomerulonephritis.  He argued for protein restriction, as was becoming accepted for chronic uraemia, but it was in acute renal failure (ARF, or AKI) that real progress was being made.

An Edinburgh diet prescription
in the 1960s.  Borst, Bull and
Addis ushered in an era of
precise dietary prescription in
renal failure. 

The year before, Geerd Borst, Professor of Medicine in Amsterdam, published a landmark paper on the management of renal failure.  In ARF he argued for radical restriction of protein and electrolytes.  20 years before it had been shown that the greatest reduction in urea production in healthy people was achieved by giving excess calories and a protein-free diet.  The excess calories reduced breakdown of endogenous protein, mostly muscle protein.  It seemed desirable to reduce this in patients with renal failure, as protein metabolism seemed to be toxic in animals and from clinical experience.  The toxin was not necessarily urea itself though Borst seemed to assume so. 

It was difficult to give enough calories to patients with severe renal failure, as they become anorexic and vomit.  However enough calories could not be given intravenously in these pre-central catheter days.  Borst described a diet of butter and sugar for patients with ARF, and described the effects in one normal individual, 3 patients with acute renal failure (ARF) and 2 with severe chronic renal failure (CRF).  Only one survived, his kidneys opening up after 5 days of anuria, but the biochemical effects were encouraging.  To improve palatability they later added some custard powder to the mix.  As recovery occurred they allowed more protein. 

Two diets for acute renal failure:

Borst, 1948 (Amsterdam) Custard powder 100g Sugar 150g Butter 100g Water 1.5 litres Given as a gruel by mouth; provided 1750 calories. No electrolytes, almost no protein.

Bull, 1949 Glucose 400g Peanut oil 100g Vitamins optional Water to 1 litre Dripped in through a nasogastric tube; 2500 calories. No electrolytes, no protein.

They had Kolff’s revolutionary dialysis machine at their disposal but found it very hard to use – “we tried to free him from some of his urea with Kolff’s artificial kidney but failed through technical difficulties and our lack of skill”.

Bull’s 1949 paper from Hammersmith, West London, changed management.  They took Borst’s observations along with those of Lattimer and others on fluid balance, and used them to develop a highly structured approach to the management of ARF.  Lattimer had noted ‘the body is not analogous to a tank into which water can be forced until it finally bursts out through he kidneys’, and described the risks of fluid excess. 

So Bull and colleagues modified Borst's unpalatable diet for administration by nasogastric tube, restricted intake to one litre and did not give any electrolytes at all, but readministered any vomitus after filtering, to minimise electrolyte loss. They reported the outcome in 11 patients with ARF caused by illegal abortion, mercury poisoning, and transfusion mismatch.  Seven survived oliguria of 7-20 days, a remarkable achievement. 

Bull’s report came from the same institution that had described the results of using Kolff’s artificial kidney the year before.  While the paper was positive, the feeling on the ground was not – there was no further use of haemodialysis there until Shackman re-established a programme to support transplantation, and it was only in 1956 that haemodialysis returned to the UK.  Conservative therapy became the accepted mode of management.  It is still effective, and it is still the only therapy available for many in developing countries.  

Borst noted that failure of dietary therapy was likely in ARF where there was muscle necrosis as in the Crush Syndrome described in West London by Bywaters, in major trauma, and if infection occurred, all of which led to increased endogenous production of urea (i.e. muscle breakdown). These limitations of conservative management led to trials of dialysis in the Korean War. 

There was to be a long wait before the role of dietary composition in chronic renal failure became as well understood. 

Further info

Addis T  1949.  Glomerular nephritis.  Macmillan, New York

Borst JGG.  Protein katabolism in uraemia.   Lancet 1948 ii 824-8

Bull GM, Joekes, AM, Lowe KG.  Conservative treatment of anuric uraemia.  Lancet 1949 ii 229-34
History of diet from the Edren History pages (www.edren.org)
Diet for chronic uraemia from this blog